CN1665484A - 暖热、无刺激性的无水润滑剂组合物 - Google Patents
暖热、无刺激性的无水润滑剂组合物 Download PDFInfo
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- CN1665484A CN1665484A CN038158752A CN03815875A CN1665484A CN 1665484 A CN1665484 A CN 1665484A CN 038158752 A CN038158752 A CN 038158752A CN 03815875 A CN03815875 A CN 03815875A CN 1665484 A CN1665484 A CN 1665484A
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Abstract
本发明涉及基本无水、无毒、无刺激的润滑剂组合物,它包含多元醇和保温剂,以及与之相关的凝胶和冻胶组合物。本发明还涉及使用这种组合物进行润滑、施用活性组分和预防或治疗痛经的方法。
Description
本申请是美国专利申请10/137509和待审美国专利申请第__号(代理人案号PPC834 CIP1)的继续部分申请,这两个专利申请在此引为参考。
发明领域
本发明涉及个人用基本无水润滑剂凝胶和冻胶组合物,当施涂到皮肤或粘膜上,特别是施涂到阴道或口腔粘膜上时,这些组合物暖热且无刺激。在某些实例中,本发明组合物基本无水,包含一种或多种多元醇。本发明还涉及可用来测试和比较本发明组合物和本领域其他已知个人用润滑剂的刺激性的方法。与以前已知的利用放热反应产生热量或用刺激物传送暖热感的组合物不同,本发明组合物利用“溶液热”产生热量。与以前已知的组合物相比,本发明组合物产生的暖热感温和且令人非常愉悦。本发明组合物对组织的润滑作用也比以前已知的暖热组合物好。此外,本发明组合物用水稀释时,其润滑性提高;而以前已知的水性组合物用水稀释时,其润滑性下降。因此,在实际应用中,本发明组合物的润滑效果比本领域以前已知的组合物好得多。
发明背景
人是温血动物,体温保持在98.6°F(37℃)恒定不变。人的皮肤和外部器官有着非常有效的循环系统和神经系统,因而人体能非常快地感觉到温度的变化。个人用润滑剂和药剂通常在室温下,即在60-80°F之间的温度下施用到人的粘膜上。由于室温与人的体温之间有明显的差异,这些润滑剂和药剂的使用者就感到非常冷。对使用者来说,这种冷的感觉是非常不舒适的。因此,人们常常尝试开发克服这种冷的感觉的产品。
本领域已知相当多的个人润滑组合物。这些组合物的范围从胶冻到液体,再到阴道栓剂,其并且为水基、油基,和硅氧烷基各不相同。如今实际使用的大部分组合物是水性胶冻或水性液体。当今几乎所有已知可用的个人润滑剂都是触摸是冷的,这是一种令人不适的感觉。
商业已知或文献描述许多组合物,它们均称在施用到皮肤或粘膜上时可带来暖热的感觉。根据作用机理,一般可将这些组合物分成几个大类。
其中有些组合物采用植物提取剂,它们对皮肤和粘膜有刺激,它们也正是利用这种刺激作用产生暖热感觉的。其他组合物声称能增加血流量,从而使组织暧热。还有一些组合物据说是根据使凝固点下降原理工作的,适合在微波炉中加热或在冰箱中冷却。有一种化妆用组合物,它能自发生热,方法是加入包含硼-硼键的化合物,它与水反应放热。
一种暖热组合物采用植物提取物或试剂,如水杨酸甲酯,它们对皮肤或粘膜有刺激作用。例如,WO97/02273a描述了用于口腔或局部组合物的磷酸盐衍生物,以产生暖热的感觉。这些组合物包含暖热组分,如香草衍生物。这些组合物还含有其他暖热剂,包括乙醇、烟酸、jambu、姜油酮、香草醇异丙基醚、姜醇、水杨酸甲酯、生姜酚、对羟基苯甲酸甲酯、姜油酮、辣椒素、二氢辣椒素、去甲二氢辣椒素、高辣素、辣椒酊剂、桉树油。
另一类暖热产品利用增加血液循环的机理。美国专利5895658,题为“施用L精氨酸使组织暧热,持续释放氧化一氮治疗糖尿病,刺激头发生长,治疗伤口的效果”,描述了能增进组织中血液流动的制剂,从而产生良好的效果,如暖热手脚的冷组织。
还有一类暖热产品利用无机化合物产生放热反应,从而放热。例如,WO200260408A1涉及化妆用无水护发组合物,所述组合物包含无机盐,如硫酸钠、硫酸钙、硫酸铝、氯化钙、氯化镁或氧化钙,或者硫酸镁。与水混合后,这些组合物可产生热量。
KR20010227018描述了放热化妆品,它包含活性沸石组合物,这种组合物能促进血液循环和新陈代谢,使皮肤产生暖热感。活性沸石包含乙氧化醇。JP63159490A涉及放热化妆用组合物,特别用于软化头发,该组合物包含还原剂,如亚硫酸钠、硫代硫酸钠、焦亚硫酸钠或亚硫酸氢钠,还包含氧化剂,如溴酸钠、溴酸钾或过溴酸钠。
EP2001306347涉及剃须用的组合物。该组合物至少包含这样一种物质,当在剃须的过程中混合时,它能发生可察觉的化学变化。此物质温度发生改变,释放出气味或进行氧化、水合、酸碱反应或放热反应。
另一类发热产品利用的机理与前面三种不同。US20020142015A1和JP2002179517a描述了用于化妆品、化妆用品、洗浴用添加剂和药物的组合物,这些组合物包含冷却剂和特定的对羟基苯甲醛衍生物。使用这种对羟基苯甲醛冷却剂的目的是在较长的时间里产生暖热效果。FR2810240A1描述了化妆用组合物,它们包含一种能吸收或释放热量的组分,从而在遇热时产生清凉效果,而在遇冷时产生暖热效果,如长链烃化合物的组合,这种组合可吸收热能,储存或交换热量。US3632516a描述了一种自热型泡沫,其通过氧化氢和硫代硫酸盐的氧化还原反应,可快速加热。
JP2001335429描述了凝胶状化妆品,它们包含40-75重量%聚乙二醇、20-55重量%甘油和羧基乙烯基聚合物。这些组合物用于产生热量,以促进疲劳状态下的血液循环和新陈代谢,在剃须时提供温暖的感觉。商业上已知的一个组合物实例,由Lexie Trading,Inc.,Fairlaw,New Jersey分售的ProsensualTM,其包含植物提取物,如桂皮(肉桂)、姜药、薄荷、檀香木、橘子和丁香,已知这些全都对皮肤有刺激。这种组合物的缺点是会刺激粘膜,对于阴道粘膜或口腔粘膜来说,这是有问题的,因为这种刺激会促使有害细菌生长,引起感染。
目前使用的另一种组合物,International,Valencia,California分售的WETTMHeating Massage Oil,采用棕榈酸视黄酯(维生素A棕榈酸酯)、扁桃(Prunusamygdalis)(李属)Amara(杏仁)、桃属gratissima(Avacado油)、澳洲竖果树种子油、kakeri竖果油、向日葵属(杂交向日葵)、大麻种子油和芦荟。已知这些组分大多数有刺激性,不适合用于粘膜上。
美国专利5513629,题为“可利用微波放热和吸热的组合物和容器,含保湿剂、凝固点下降剂、凝胶密封剂、聚丙稀酰胺吸收剂、玉米淀粉粘结剂、矿物油和增塑剂的柔韧凝胶,它们的耐久性和功效”,描述了蒸气温度较的组合物,因此它们适合在微波炉中加热或在冰箱中冷却,并适合放置在合适的容器或乙烯基包装物中,如冷-热包装物,但人不宜消费或使用。
但是,前述组合物没有一个实际是“热的”,或者说温度高于产品的室温或环境温度。
美国专利4110426,题为“用自发生热化妆品、有机硼-氧-硼化合物调理皮肤和头发的方法”,描述了非水性组合物,如剃须膏,这些组合物中含有一种化合物,该化合物至少含有一个硼-氧-硼键,如三乙氧基环硼氧烷,因而这些组合物能够自热。含硼化合物与水或其他含质子物质发生放热反应,从而提高温度。这些组合物不适合用于阴道或口腔,因为含硼化合物可能对人的生殖系统有潜在毒性(Fail PA等,含硼化合物的一般毒性、对生殖系统的毒性、对发育的毒性和对内分泌的毒性,Reprod toxicol 12:1,1-18,1-2月,1998)。
为治疗,已经用物理能量形式来增强物质迁移通过膜。这种能量形式包括电能、超声波和热能(例如热辅助给药)(Sun的综述“用热、超声波和电的物理方法增强皮肤吸收”,Transdermal and Topical Drug Delivery Systems,Interpharm Press,Inc.,1997,pp.327-355)。对给药体系或配剂,以及皮肤或粘膜组织进行局部加热,不仅能够提高药物分子的热力学能量和膜的渗透性,以促进药物通过膜屏障,而且能增进组织中的血液循环,使药物快速离开局部组织,进入系统循环。这两个过程都能增进药物的吸收。实验证据表明,低热(即组织温度低于约42℃)可显著提高药物通过皮肤的吸收。
美国专利5658583描述了一种能够增进药物对皮肤渗透的发热装置。该装置包括一个薄的储药池和发生氧化反应的发热室,二者通过非渗透壁隔开。储药池装有预定量的含药剂的制剂。发热/温度调节室含有发热介质,该介质由碳、铁、水和/或盐组成,它与空气中的氧接触后就得到活化。但是,考虑到安全因素,这样复杂的发热装置是不适合用在阴道或口腔中的。
局部加热方法(如腹部加热贴剂)也用于治疗痛经或月经痉挛,并已取得一些疗效(Akin MD等,连续局部低热在治疗痛经,Obstet Gynecol 97:3,343-9,3月,2001)。
美国专利6019782描述了一次性体热垫,它们通过氧化反应生热,贴在腹部皮肤上时,可用于缓解痛经。目前美国市场上有一种用于治疗痛经的商业产品——ThermaCare®空气活化加热包,由宝洁公司(Cincinnati,OH)生产的月经痉挛缓解垫,它们基于腹部加热。但是,目前还没有通过内部局部加热治疗痛经的产品,也没有这方面的描述。
发明概述
本发明的组合物和方法涉及基本无水、无刺激凝胶和冻胶组合物。本发明的组合物和方法包含纤维素胶凝衍生物和多元醇。纤维素胶凝衍生物宜为水胶体。本发明组合物可用作暖热润滑剂组合物,它们无毒无刺激,可用作与皮肤或粘膜接触的个人用润滑剂。与水混合后,本发明凝胶和冻胶组合物温度升高,或者说产生热量。对于施用了这些组合物的组织来说,这会产生缓解的效果。这基本上消除了常用个人用润滑剂使用时所带来的冰冷的感觉。
本发明组合物具有优良的润滑性。本发明凝胶和冻胶组合物比目前市场上可得到的水性润滑剂产品具有更好的润滑作用。本发明组合物,特别是本发明的冻胶组合物的新颖之处在于,它们用水稀释后润滑效果增加。已知的市售水性组合物用水稀释后,其润滑性下降。当本发明组合物用于湿润的阴道或口腔时,这一点就尤其有利,因为它们与阴道或口腔中的水分接触后,将变得更加润滑。
尽管一般认为无水组合物对皮肤和粘膜会产生刺激,但让人意外的是,本发明的凝胶和冻胶组合物没有刺激性。
本发明组合物可施用在皮肤或粘膜上,宜施用在阴道或口腔粘膜上。本发明组合物宜基本无水,且宜至少包含一种多元醇。
我们在理论上认为,当本发明组合物所包含的多元醇与水或人体的水分接触时,它们将与环境水分子反应,使温度升高或者产生热量,因此对施用了这些组合物的组织具有缓解作用。
出人意料的是,与通常认为组合物中的多元醇对粘膜有刺激的观点相反,已发现本发明含这种多元醇的组合物没有刺激性。我们在理论上认为,本发明组合物和方法中所用水胶体与水接触后溶胀,产生润滑涂层凝胶。此涂层实际上阻断了本发明组合物中其他无水成分的刺激作用。此外,由于本发明组合物中所用多元醇是保湿剂和增湿剂,当水胶体溶胀并在粘膜组织上形成薄膜时,该膜保持了组织表面上的增湿剂。因此,本发明组合物克服了各种因素,包括绝经和衰老以及各种疾病引起的干燥状况,如阴道干燥和口腔干燥。
因此,本发明组合物对皮肤和粘膜非常温和。将本发明组合物施用到口腔粘膜上后,将会产生缓解效果,起缓解口腔和咽喉的轻度刺激的作用。
本发明组合物中的多元醇组合也可用作载体,溶解其他不溶药物,包括(但不限于)杀真菌剂、杀菌剂、抗病毒剂、止痛剂、消炎类固醇、避孕药、局部麻醉剂、荷尔蒙等。
本发明组合物宜保持酸性pH。酸性pH非常有利于保持阴道和口腔菌丛健康,特别是保持阴道中的乳酸杆菌。已知常用的酸或缓冲剂不溶于无水组合物。本发明组合物宜包含可溶于其中的有机酸,以保持酸性pH。有机酸宜为乳酸。乳酸不仅溶于本发明的无水组合物,而且它是人体组织产生的天然酸,能非常安全地用于本发明组合物。这种有机酸特别适合用作酸化试剂,帮助降低施用本发明组合物的组织的pH。这将有助于维持粘膜的天然酸性环境,促进合适菌丛的生长。
本发明组合物还宜包含保温剂,它的作用是在本发明组合物施用在皮肤或粘膜上后,通过保持热量,从而保持升高的温度。宜用蜂蜜作保温剂。
附图简述
图1为采用实施例1中的组合物时,活表皮细胞%与接触时间的关系图。
图2为采用实施例2中的组合物时,活表皮细胞%与接触时间的关系图。
图3为采用最新技术的无刺激产品(K-Y Liquid®)时,活表皮细胞%与接触时间的关系图。
图4为图采用最新技术的暖热产品(Prosensual®)时,活表皮细胞%与接触时间的关系图。
图5为比较实施例1的组合物和销售的三个主要个人用润滑剂的润滑性与时间(秒)的关系图。
优选实例详述
本发明组合物基本上无水,其含水量宜少于约20%,更宜少于约5%,最好少于约3%。
本发明组合物宜至少包含一种多元醇,更宜包含两种多元醇。本发明组合物中的至少一种多元醇宜为聚(亚烷基)二醇或其它醇,该其这醇选自甘油、丙二醇、丁二醇、己二醇或各种分子量的聚乙二醇等,以及它们的组合。本发明组合物更宜包含聚乙二醇;聚乙二醇最好选自聚乙二醇400或聚乙二醇300。本发明组合物所含多元醇约占组合物的80-98重量%。
本发明组合物还宜包含一种或多种由纤维素衍生的水溶性成膜聚合物、树胶、壳聚糖等。这种由纤维素衍生的聚合物宜为羟烷基纤维素聚合物。羟烷基纤维素聚合物更宜选自:羟乙基纤维素、羧甲基纤维素、羟丙基纤维素和羟丙基甲基纤维素等。羟烷基纤维素聚合物最好为羟丙基纤维素,如Klucel®,可购自Hercules Incorporated,Wilmington,Delaware。除羟丙基纤维素以外大多数纤维素衍生聚合物可溶于水,但不溶于无水溶剂,羟丙基纤维素则完全溶于本发明组合物中的无水多元醇部分。本发明组合物宜包含约0.15-0.6重量%羟丙基纤维素,以产生可灌的凝胶,宜包含约1-4重量%羟丙基纤维素,以产生触变性冻胶。
本发明组合物还包含保温剂。保温剂更宜为蜂蜜或异丙醇与饱和高分子量脂肪酸,如肉豆蔻酸或棕榈酸形成的酯,例如肉豆蔻酸异丙酯和棕榈酸异丙酯。本发明组合物中保温剂的含量应约为1-5重量%。
令人意外的是,本发明组合物自身具有防腐性能,不需要添加防腐剂。但是,也可以加入防腐剂,以再确保抗微生物生长。防腐剂可选自本领域技术人员已知的防腐剂,包括(但不限于)以下物质中的一种或多种:对羟基苯甲酸甲酯、苯甲酸、山梨酸、没食子酸、对羟基苯甲酸丙酯等。本发明组合物所含防腐剂宜约占组合物的0.01-0.75重量%。
本发明组合物还宜包含酯。所述酯更宜为脂肪酸酯。所述酯最好包括(但不限于)硬脂酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、月桂酸异丙酯等。所述酯最好为肉豆蔻酸异丙酯。
本发明组合物可包含一种或多种水溶性纤维素衍生聚合物、树胶、壳聚糖等。这种聚合物为本发明组合物提供粘度和生物粘合性。这种纤维素衍生聚合物宜为羟烷基纤维素聚合物。羟烷基纤维素聚合物更宜为羟丙基纤维素或Klucel®,可购自Hercules Incorporated,Wilmington,Delaware。
从理论上讲,本发明组合物所用多元醇可用作暖热和生热剂。蜂蜜的作用是作为保温剂,防止该组合物变得太冷。酯宜为脂肪酸酯,作为润肤剂和润滑剂。纤维素聚合物可用作增粘剂。本发明组合物的独特之处在于,它们对使用者的组织,尤其是口腔和阴道粘膜产生润滑、温暖和缓解作用,而不会带来冷的感觉。此外,它们是滑润的。
本发明组合物可以是液体、半固体或固体,具体取决于其具体预定用途。本发明组合物可配成糖浆状液态凝胶、可潜的凝胶或粘稠冻胶。其粘度宜约在1000-7000cp(厘泊)之间,冻胶物的粘度宜在60,000-500,000厘泊之间。本发明组合物也可配成柔软或坚硬的明胶胶囊、栓剂,也可浸渍入织物或聚合物中。
本发明组合物可用作个人用润滑剂,它可给人带来暖热的感觉。本发明组合物产生的暖热感对它们所施用的皮肤或粘膜能产生缓解作用。本发明组合物还具有可口的甜味,这特别有利于口服这些组合物。
本发明组合物也可用作个人用增湿剂,当施用在阴道或口腔粘膜中时,可带来暖热感。可用它们作增湿剂,传递暖热感,缓解阴道干燥或口腔干燥。
本发明组合物也可用作载体,向生物膜输送药物或其他治疗用药剂,包括(但不限于)荷尔蒙、抗微生物剂、抗菌剂、抗生素、非类固醇消炎剂、杀精子剂、免疫调节剂(imunodilator)、麻醉剂、植物提取物、维生素、皮质类固醇或杀真菌剂等。
杀真菌剂宜为吡咯或咪唑,包括(但不限于)咪康唑、益康唑、特康唑、沙康唑、伊曲康唑、布康唑、克霉唑、噻康唑、氟康唑和酮康唑、伏立康唑【vericonazole】、芬替康唑、舍他康唑、泊沙康唑、联苯苄唑、奥昔康唑、硫康唑、elubiol、伏立康唑(vorconazole)、异康唑、氟曲马唑和它们的药用可接受的盐等。其他杀真菌剂可包括烯丙胺或其他化学物质,包括(但不限于)temafine、萘替芬、阿莫罗芬、布替萘芬、环吡酮、灰黄霉素、十一烯酸、卤普罗近、托萘酯、制霉菌素、碘、利洛吡司、BAY 108888、绛红霉素和它们的药用可接受的盐。
本发明的另一实例是用于外阴或其他粘膜且包含一种或多种抗生素的组合物。抗生素可选自(但不限于)甲硝唑、克林霉素、替硝唑、奥硝唑、塞克硝唑、refaximin、丙大观霉素、绛红霉素和它们的药用可接受的盐等。
本发明组合物的另一实例包括用于外阴或其他粘膜且包含一种或多种抗病毒剂的组合物。抗病毒剂宜包括(但不限于)免疫调节剂,更宜为咪喹莫特、其衍生物、普达非洛、鬼臼树脂、干扰素α、reticolos、西多福韦、壬苯醇醚-9和它们的药用可接受的盐等。
本发明组合物的其他实例是包含一种或多种杀精子剂的组合物。杀精子剂宜包括(但不限于)壬苯醇醚-9、辛苯昔醇-9、十二烷基乙二醇单月桂酸酯、Laureth 10S和甲氧基聚氧乙二醇550月桂酸酯等。
本发明组合物的其他实例是包含抗微生物的组合物。抗微生物剂宜包括(但不限于)氯己啶葡萄糖酸酯、聚苯乙烯磺酸钠、纤维素硫酸钠、微米级和亚微米级银粒子、银盐和本领域已知的其他杀菌剂。
本发明组合物的其他实例是包含局部麻醉剂的组合物。局部麻醉剂宜包括(但不限于)苯佐卡因、利多卡因、地布卡因、苄醇、樟脑、间苯二酚、薄荷醇和盐酸二苯基羟胺等。
本发明组合物还包括植物提取物,如芦荟、金缕梅、甘菊、氢化大豆油和胶态燕麦、维生素(如维生素A、d或E)和皮质类固醇(如醋酸氢化可的松)。
本发明组合物和方法的另一实例包括用于外阴且包含一种或多种荷尔蒙的组合物,用于治疗妇女雌激素分泌方面的疾病,如因妇女阴道萎缩而需要补充雌激素。荷尔蒙宜包括(但不限于)这样的雌激素,它们选自雌二醇、苯甲雌二醇酯、环丙酸雌二醇、二丙酸雌二醇、庚酸雌二醇、轭合雌激素、雌三醇、雌酮、硫酸雌酮、炔雌醇、雌呋酯、炔雌醚和美雌醇。
本发明组合物和方法的另一实例包括用于外阴且包含一种或多种止痛和/或非类固醇消炎剂的组合物,用于治疗痛经或月经痉挛。止痛和非类固醇消炎剂宜包括(但不限于)阿司匹林、布洛芬、吲哚美辛、保泰松、溴芬酸、 fenamate、舒林酸、萘丁美酮、酮咯酸和萘普生等。
在本发明组合物和方法的另一种实例中,组合物可用于治疗妇女本身的性功能障碍,因为它们可提高用药部位的温度,从而增进这些部位的血液流动。或者,它们可包含本领域技术人员已知的用于治疗妇女性功能障碍(包括各种妇女性功能障碍,如妇女性欲唤起困难、性欲低下、性高潮困难等)的药剂,以及用于治疗性交困难和/或阴道痉挛或外阴阴道炎(mlvodynia)的药剂,以缓解性交时的疼痛。这种药剂包括荷尔蒙,如雌激素、前列腺素、睾丸激素;钙通道阻断剂、胆碱能调节剂、α肾上腺素能受体拮抗剂、β肾上腺素能受体拮抗剂、cAMP依赖性蛋白激酶活化剂、过氧化物清除剂、钾通道活化剂、类雌激素化合物、类睾丸激素化合物、苯并二氮杂䓬、肾上腺素能神经抑制剂、HMG-CoA还原酶抑制剂、平滑肌松弛剂、腺苷受体调节剂和腺苷酰环化酶活化剂。这种药剂包括5-磷酸二酯酶-5抑制剂等。
本发明组合物和方法的另一种实例包括用于口腔和外阴和其他粘膜的组合物,所涉及的方法可增进粘膜从所施用组合物中吸收活性药剂,具体过程是组合物中的多元醇与粘膜上的水分作用后放热,从而提高了组合物和粘膜组织的温度。
本发明组合物的另一实例包括用于外阴的组合物,该实例涉及通过暖热阴道内部来预防和/或治疗痛经的组合物和方法。组合物宜将阴道内部温度加热到约37-42℃之间,更宜加热到约38-41℃之间。本发明用于此方法的组合物可任选包含用于治疗痛经的活性剂,如止痛剂和非类固醇消炎剂。本发明组合物可用施用器直接施用到阴道内,或者先浸渍在阴道器件如卫生栓上,然后施加到阴道中。
本发明组合物在生产时可涂敷在卫生栓上,或者分散在整个吸收性卫生栓材料上,或者封闭在卫生栓芯子里面。本发明用于温热卫生栓以预防和/或治疗痛经的组合物宜包含各种分子量的聚乙二醇的混合物,所述聚乙二醇由陶氏化学公司(Midland,MI)生产,商品名有CARBOWAX SENTRY PEG 300 NF、CARBOWAX SENTRY PEG 400 NF、CARBOWAX SENTRY PEG 600 NF、CARBOWAX SENTRY PEG 900 NF、CARBOWAX SENTRY PEG 1000 NF、CARBOWAX SENTRY PEG 1450 NF、CARBOWAX SENTRY PEG 3500 NF、CARBOWAX SENTRY PEG 4000 NF、CARBOWAX SENTRY PEG 4600 NF和CARBOWAX SENTRY PEG 8000 NF。本发明用于预防和治疗痛经的组合物可包含一种或多种水溶性纤维素衍生聚合物和树胶,它们在多元醇,如甘油、丙二醇和聚乙二醇周围形成凝胶,从而减少多元醇的溶解,延长溶解热的释放,将升高的温度调节在较佳范围之内。
本发明还涉及用实施例1所述EpiDermTM Skin模型分析法测定和比较特定来源的药剂,如施用在皮肤或粘膜细胞上的组合物所引起的刺激的相对量。以下实施例1解释了本发明方法的使用。
实施例1:用EpiDermTM Skin模型分析法测试润滑剂的刺激性
称作EpiDermTM Skin模型分析法的方法用人类皮肤的上皮细胞可购自MatTek公司作为靶细胞。此分析法见述于Berridge,M.V.等(1996),TheBiochemical and Cellular Basis of Cell Proliferation Assays That Use TetrazoliumSalts(用四唑鎓盐进行细胞增殖分析的生化和细胞学基础),Biochemica 4:14-19。实验材料直接施用在上皮细胞的培养表面上。此前末曾用此实验方法测定实验材料的毒性。实验材料的毒性根据组织生存力与时间的相对关系来评价。实际组织生存力根据对照样品和经过处理的实验培养样品中MTT的微粒体酶随NAD(P)H减少的情况确定。本分析法中所用负对照样品是去离子水,所用正对照样品是Triton X-100。与样品接触的培养细胞分别培养4、8、16和24小时,分析MTT减少的情况。所得数据绘制在图1-4中,它们是相对生存量(MTT相对减少量)-接触时间关系图。本分析中的相对刺激性用24小时内上皮细胞的生存百分率表示。有较高相对生存率的产品,则其毒性或刺激性较小,而有较低生存率的产品则其毒性或刺激性较大。本发明四种组合物的生存率在81.3-90.3%之间,表明本发明组合物基本上没有刺激。
图1-4总结了EpiDermTM Skin模型生物分析的结果。利用所得数据,绘制4-24小时的活细胞%与接触时间的曲线。图1和2分别代表本发明的两种组合物,即组合物1和组合物2的结果。图3代表K-Y Liquid®的结果,K-Y Liquid®是销售确认的个人用润滑剂。K-Y Liquid®动物和人类实验已经证实是安全、无刺激的,人们已经用了很长时间。K-Y Liquid®的结果表明与细胞接触24小时后,细胞生存率仍高达100.3%(图3)。
本发明实施例1(图1)和本发明实施例2(图2)分别显示活细胞为91.1%和96.9%。图4表明商业上已知的暖热组合物的结果。此产品利用植物材料,如肉桂、丁香、姜和橘子及其他物质产生暖热效果。结果表明,此产品与细胞接触24小时后的活细胞仅为37.6%。这表明这种组合物可能对皮肤和粘膜有刺激。本发明组合物1和组合物2分别具有91.1%和96.9%的活细胞,这们实际上没有刺激。正对照样品(Triton X-100)与细胞接触8小时后活细胞这们仅为22.4%。
实施例2:暖热的产生
本发明组合物是无水的,包含一种或多种多元醇。与水混合后,本发明组合物所用多元醇将使温度升高,对施用这些组合物的组织产生缓解作用。在实际应用中,本发明组合物与阴道或口腔粘膜中的水分相互作用,使温度升高或产生暖热的感觉。
“生热”数据列于表1。本发明组合物1和组合物2中每种组分各取20ml与20ml水混合,由此可得到表中数据。在将水加入产品之前,分别记录产品和水的温度。加入水后,将混合物搅拌2分钟,记录实际温度。组合物1的组分是甘油、丙二醇和蜂蜜。从表1可以清楚看到,与水混合后,甘油混合物的温度升高9.0°F,丙二醇混合物的温度升高13.5°F,聚乙二醇400混合物的温度升高17.0°F,本发明实施例1的组合物与水形成的混合物的温度升高12.5°F。根据温度的升高和组合物中各组分的%(w/w)量,可计算出组合物1的温度升高10.875°F。组合物1实际记录的温度升高12.5°F,比预计的高1.625°F,这表明各组分混合后,温度会有意外的升高。
每种产品与水等量混合后的生热数据(以温度的升高表示,单位°F)
产品名 | 产品温度(°F) | 水温(°F) | 预计平均温度(°F) | 实际温度(°F) | 温度升高量(°F)(预计-实际) |
甘油分析 | 69.0 | 71.0 | 70.0 | 79.0 | 9.0 |
丙二醇分析 | 72.4 | 71.0 | 71.7 | 85.2 | 13.5 |
蜂蜜 | 74.0 | 71.0 | 72.5 | 74.0 | 1.5 |
K-Y Warm® | 74.0 | 71.0 | 72.5 | 85.0 | 12.5 |
肉豆蔻酸异丙酯 | 75.0 | 74.1 | 74.5 | 75.2 | 0.7 |
聚山梨酯60 | 70.9 | 74.1 | 72.5 | 83.1 | 10.6 |
聚乙二醇400 | 72.0 | 71.0 | 71.5 | 88.5 | 17.0 |
计算温度的升高:为根据每种组合物确定预计温度的升高,将这种组合物中每种组分所占百分数乘以该组分单独产生的温度升高量,得到它预计对温度升高的贡献。将这些值相加,就可计算出预计的升温总量。然后可将这些值与每种组合物实际产生的温度升高量作比较。例如,上表中“K-Y Warm®”组合物所产生的计算升温量可计算如下,并与实际升温量作比较,以确定该组合物意外较高的生热:
丙二醇(13.5的50%)=6.75
甘油(9.0的45%) =4.05
蜂蜜(1.5的5%) =0.075
总计 10.875
差值:12.5-10.875=1.625
实施例3:含水量对生热的影响
本发明组合物的暖热作用来自它们与水分或水接触后产生的溶解热。需要注意的是,偶然沾染水或与过量的水分接触时间长,产品的暖热能力将受到负面影响。根据本实施例,本发明组合物中的加水量约在1-10%之间,如表2所示。各组分充分混合,样品在室温下放置24小时,然后根据下一段所述方法测定生热程度。结果显示,升温量随着加水量成比例下降,但加水量约为10%时,温度仍能升高8.5°F。
本实施例的结果列于表2。
表2:含水量对K-Y Warm®生热程度的影响
产品名 | 样品温度(°F) | 水温(°F) | 预计平均温度(°F) | 时间温度(°F) | 升温量(°F)(预计温度—实际温度) |
无水 | 73.80 | 70.00 | 71.90 | 83.50 | 11.60 |
1%的水 | 73.90 | 70.00 | 71.95 | 82.20 | 10.25 |
2%的水 | 72.30 | 70.00 | 71.95 | 81.70 | 9.85 |
3%的水 | 72.30 | 70.00 | 71.15 | 80.40 | 9.25 |
4%的水 | 72.20 | 70.00 | 71.10 | 80.70 | 9.60 |
5%的水 | 71.60 | 70.00 | 70.80 | 80.40 | 9.60 |
6%的水 | 71.60 | 70.00 | 70.80 | 80.40 | 9.60 |
7%的水 | 71.50 | 70.00 | 70.75 | 80.20 | 9.45 |
8%的水 | 71.60 | 70.00 | 70.80 | 80.20 | 9.40 |
9%的水 | 70.90 | 70.00 | 70.45 | 79.50 | 9.05 |
10%的水 | 70.50 | 70.00 | 70.25 | 79.00 | 8.50 |
实施例4:人使用时的暖热感觉
246个受试者进行人使用的研究。本研究得到的数据列于表3。要求受试者使用本发明组合物。要求他们回答三个有关使用该产品时暖热感觉的问题:
1.接触时是否暖热?
2.感觉暖热吗?
3.没有感觉到冷吧?
要求受试者将其回答写成“优”、“很好”、“良”、“中”和“差”。肯定的回答列于表3。
表3:在人使用研究中246个受试者使用本发明实施例1组合物时的暖热感觉
所提问题 | 肯定回答(%) |
接触时是否暖热? | |
优 | 25.12 |
很好 | 31.88 |
良 | 24.64 |
总计 | 81.64 |
感觉暖热吗? | |
优 | 30.88 |
很好 | 28.92 |
良 | 25.98 |
总计 | 85.78 |
没有感觉到冷吧? | |
优 | 54.37 |
很好 | 29.61 |
良 | 10.19 |
总计 | 94.53 |
从上表3可以看出,关于产品“接触时是否暖热”,81.64%的受试者作了肯定的回答。85.78%的受试者认为本产品“感觉暖热”,94.53%的受试者记录该产品“没有感觉到冷”。
实施例5:润滑性的比较
Ahmad等在美国专利6139848(在此引为参考)。中描述了测定商业上已知的各种个人用润滑剂的润滑性。在所述测定方法中,各种市售个人用润滑剂的润滑性均测定300秒(5分钟)。该专利所述润滑性数据表明,在300秒的测定时间中,K-Y Liquid®润滑剂比竞争产品具有更高的润滑性和更长的持续时间。美国专利6139848所列润滑性数据在实验的“推”的阶段具有负号(-),在“拉”的阶段具有正号(+)。本发明组合物用美国专利6129848所述润滑性测试方法测定。但是,测定时间成功地延长到16分钟(960秒),并处理数据以“曲线拟合”来消除负号(-)。本发明组合物1的润滑性数据与图5中K-Y Liquid®的数据进行了比较。数据显示,本发明组合物1比K-Y Liquid®具有更高的润滑性,而且组合物1将高润滑性保持长达16分钟(960秒),因此其持续时间更长。
实施例6:溶解热
据信,本发明组合物的暖热效果由溶解热产生,而不是为放热反应创造条件。放热反应造成放热是因为两种化学物质之间的化学反应,并且该放热反应是无法控制的。这样的放热反应会产生新的产物或新化学物质,其中有些可能对人体组织不利。与此不同,由于不同分子和相同分子之间的吸引力不同,在形成溶液时会有能量的改变。具体说来,相混合的每种组分的分子之间发生断键,所得混合物或溶液中相邻分子之间形成新键。此机理不同于反应热,因为构成分子的原子没有发生由反应物形成产物的化学重排,。从以下实验可以看出,溶解热产生的最大热量或最大升温不超过18.8°F,这使得这些组合物非常温和和安全。
本发明组合物(以下实施例9中的组合物15)在例如阴道液体(“XH2O”)中的溶解过程可用如下物理方程式表示:
名称“组合物15(XH2O)”表示产物是1(mol)组合物15在X(mol)H2O中形成的溶液。因此,使用本发明组合物,即组合物15作个人用润滑剂,不会改变自然存在的阴道液体的存在量,它只是与之形成溶液。
使用本发明组合物时产生的热量可能带来的最大升温量可利用热力学原理测定。例如,当本发明组合物与水接触形成溶液时,它释放的热量可利用差示扫描量热法(DSC)表征。在此测定方法中,当一薄层具体组合物施加到一薄层水中时,测定释放的能量。典型的测定结果示于图6。放热峰(即倒峰)的面积代表本发明组合物与水形成溶液的过程中释放的总能量。表1列出了这一系列实验所释放的能量。
表1:组合物15/水所释放热量的DSC测定结果总结
实验编号 | 本发明组合物(mg) | 释放的能量(mJ) |
1 | 17.85 | 398.878 |
2 | 22.5 | 355.108 |
3 | 28.32 | 267.229 |
平均值 | 22.89 | 340.405 |
标准偏差 | 5.25 | 67.045 |
DSC所测定的放热量表示阴道组织表面上所能观察到的最大能量,这是因为在形成溶液的过程中由DSC所测定的进入薄水膜的热通量(能通量)等于阴道组织表面液体中的热通量(能通量)。因此,可用如下热力学原理计算最大可能升温量:
Qmax=CpmΔTmax (式1)
式中,Qmax表示组合物15与水接触(形成溶液)时释放的最大能量;Cpm表示组合物15和水的溶液的热容;ΔTmax表示最高升温量。因此,对式1移项,我们可以根据已知或测定的最大释放能量和组合物15的溶液的热容,计算ΔTmax、最大升温量,即
ΔTmax=Qmax/Cpm (式2)
根据假定正态分布,可利用表1中的实验结果得到最差情况下最大值Qmax的估计值,即
Qmax={平均的实验释放能+3x(实验释放能的标准偏差)/(组合物15的平均量)}
={(340.405mJ)+(3)x(67.045mJ)}/(22.89mg)
=(541.539mJ/22.89mg)
(式3)
(以此作为上限,代表正态分布99.73%的置信度上限。)
对于Cpm,组合物15较小的Cp值和水的Cp值可用来得到最差情况下的最小值的估计值。由于
Cp(组合物15)=0.54cal/(g·℃)
Cp(组合物15)=1.00cal/(g·℃)
则
Cpm(最差情况下的最小值)=0.54cal/(g·℃)
(等式4)
因此,由组合物15所产生的热量在最差情况下可能引起的最大升温量的估计值可利用式2、3和4得到,即
ΔTmax=Qmax/Cpm
=[(541.539mJ)/(22.89mg)]/(0.54(g·℃)x0.23901cal/J)
=10.5℃或
=18.8°F
因此,用组合物15所释放的最大热量最多约为10.5℃或18.8°F,热量增加较少,表明本发明组合物带来的升温对使用者是安全和舒适的。
实施例7:暖热的产生
根据以下方法测定组合物10、11和12,以确定所述组合物与水混合后产生的生热程度。数据来自20ml每种组合物与20ml水的混合。将水加入组合物之前,记录组合物和水的温度。加水后,搅拌混合物2分钟,记录实际温度。所得结果列于下表:
每种组合物和水的等量混合的生热(温度升高°F)数据
产品名 | 产品温度(°F) | 水温(°F) | 预计平均温度(°F) | 实际温度(°F) | 温度升高量(°F)(预计-实际) |
本发明组合物的升温量 | |||||
组合物10 | 73.00 | 70.3 | 71.6 | 87.3 | 15.7 |
组合物11 | 73.00 | 70.3 | 71.6 | 83.2 | 11.6 |
组合物12 | 73.00 | 70.3 | 71.6 | 87.1 | 15.5 |
组合物中各组分的升温量 | |||||
聚乙二醇400 | 72.0 | 71.0 | 71.5 | 88.5 | 17.0 |
丙乙醇 | 72.4 | 71.0 | 71.7 | 85.2 | 13.5 |
甘油 | 69.0 | 71.0 | 70.0 | 79.0 | 9.0 |
我们计算了组合物10、11和12的升温量:
组合物10
丙二醇(13.5的38%)=5.13
聚乙二醇400(17.0的61.5%)=10.45
总计 15.58°F
组合物11
组合物11计算得到的升温量为15.58°F。
组合物12
组合物12计算得到的升温量为15.15°F。
三种组合物的计算升温量非常接近于实际升温量。
实施例8:比较润滑性
用上面实施例3所述测定、比较各种个人用润滑剂的润滑性的方法,测定了本发明组合物的润滑性。下面概括测定结果:
本发明凝胶组合物的润滑性能类似于Ahmad等的美国专利6139848所述的水凝胶组合物。在图7中,同时测定了市售KY®Telly的润滑性和它用水1∶1稀释后的润滑性。稀释后,润滑性没有显著增加。
本发明冻胶组合物比商业上已知最新技术的水性冻胶物具有更好的润滑性。测定了本发明组合物14刚制备好时的润滑性和用水1∶1稀释后的润滑性。让人意外的是,其润滑性在稀释后显著提高(约4倍)。这些数据示于图8。
因此,本发明冻胶组合物用水1∶1稀释后,变得更加润滑,或者说润滑性提高。
图9比较了KY®Telly和组合物14在初始状态时的润滑性。图10示出了本发明的两种暖热凝胶组合物,组合物13和14的润滑性,显示出它们的高润滑性。
图11所示为KY*Ultragel和稀释的组合物14。
实施例9:本发明组合物
本发明组合物按如下方法制备:先混合丙二醇和甘油,在同一容器中向混合物中加入防腐剂和保温剂,然后将混合物加热到约35-45℃,使防腐剂完全溶解,再冷却混合物。在高速搅拌器中,在约60-70℃温度下混合丙二醇、聚乙二醇和羟丙基纤维素,直到制得调匀的凝胶或冻胶来制备凝胶和冻胶组合物。将所得凝胶或冻胶冷却到约45-55℃,加入乳酸。继续搅拌混合物约15分钟,或直到乳酸溶解。然后将混合物冷却到室温。
组合物1:
丙二醇 50.00%
甘油 45.00%
蜂蜜 5.00%
组合物2:
丙二醇 50.00%
甘油 20.00%
肉豆蔻酸异丙酯 27.00%
聚山梨酯60 3.00%
组合物3:
丙二醇 95.00%
蜂蜜 5.00%
组合物4:
丙二醇 50.00%
甘油 20.00%
肉豆蔻酸异丙酯 29.50%
Klucel HF 0.50%
组合物5:
丙二醇 99.50%
Klucel HF 0.50%
组合物6:
丙二醇 49.80%
甘油 45.00%
蜂蜜 5.00%
防腐剂 0.20%
组合物7:
硝酸咪康唑 2.00%
丙二醇 49.80%
甘油 43.00%
蜂蜜 5.00%
防腐剂 0.20%
组合物8:
氟康唑 2.00%
丙二醇 49.80%
甘油 43.00%
蜂蜜 5.00%
防腐剂 0.20%
组合物9:
甲硝唑 3.00%
丙二醇 49.80%
甘油 42.00%
蜂蜜 5.00%
防腐剂 0.20%
组合物10(凝胶):
丙二醇 38.00%
聚乙二醇400 61.05%
乳酸 0.20%
羟丙基纤维素 0.75%
组合物11(冻胶):
丙二醇 37.00%
聚乙二醇400 61.05%
乳酸 0.20%
羟丙基纤维素 0.75%
组合物12(凝胶):
丙二醇 48.00%
聚乙二醇400 51.30%
乳酸 0.20%
羟丙基纤维素 0.50%
组合物13(冻脑):
丙二醇 48.55%
聚乙二醇400 50.00%
乳酸 0.20%
羟丙基纤维素 1.25%
组合物14(冻胶):
丙二醇 98.55%
乳酸 0.20%
羟丙基纤维素 1.25%
组合物15(冻胶):
聚乙二醇400 98.55%
乳酸 0.20%
羟丙基纤维素 1.25%
组合物16(凝胶):
聚乙二醇400 99.50%
乳酸 0.20%
羟丙基纤维素 0.30%
组合物17(凝胶):
丙二醇 74.50%
甘油 25.00%
乳酸 0.20%
羟丙基纤维素 0.30%
组合物18(凝胶):
丙二醇 74.50%
聚乙二醇400 25.00%
乳酸 0.20%
羟丙基纤维素 0.30%
组合物19(凝胶):
丙二醇 69.50%
聚乙二醇400 15.00%
甘油 15.00%
乳酸 2.00%
羟丙基纤维素 0.30%
组合物20(冻胶):
丙二醇 73.55%
聚乙二醇400 25.00%
乳酸 0.20%
羟丙基纤维素 1.25%
Claims (19)
1.一种基本无水的润滑剂组合物,它包含至少一种多元醇和胶凝剂。
2.权利要求1所述的组合物,其特征在于所述组合物还包含pH调节剂。
3.权利要求1所述的组合物,其特征在于所述多元醇选自甘油、亚烷基二醇、聚乙二醇和它们的混合物。
4.权利要求1所述的组合物,其特征在于所述胶凝剂是羟丙基纤维素。
5.权利要求3所述的组合物,其特征在于所述亚烷基二醇选自丙二醇、丁二醇和己二醇。
6.权利要求4所述的组合物,其特征在于所述聚乙二醇选自聚乙二醇300、聚乙二醇400和它们的混合物。
7.权利要求1所述的组合物,其特征在于所述胶凝剂是乳酸。
8.权利要求5所述的组合物,其特征在于所述组合物包含约75-99重量%的多元醇、约0.1-4重量%的羟丙基纤维素和约0.1-1重量%的乳酸。
9.权利要求1所述的组合物,其特征在于所述组合物的粘度约为1000-7000厘泊。
10.权利要求1所述的组合物,其特征在于所述组合物的粘度约为60000-500000厘泊。
11.权利要求1所述的组合物,其特征在于它还包含抗微生物剂。
12.权利要求11所述的组合物,其特征在于所述抗微生物剂是抗真菌剂。
13.权利要求11所述的组合物,其特征在于所述抗微生物剂是抗细菌剂。
14.权利要求11所述的组合物,其特征在于所述抗微生物剂是抗病毒剂。
15.权利要求1所述的组合物,其特征在于所述组合物还包含杀精子剂。
16.权利要求1所述的组合物,其特征在于所述组合物还包含局部麻醉剂。
17.一种治疗或预防痛经的方法,它包括在阴道内施用权利要求1所述的组合物。
18.权利要求1所述的组合物,其特征在于所述组合物与水分接触后使温度升高。
19.权利要求7所述的组合物,其特征在于将所述组合物的pH调节到约2-6之间。
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US8770201B2 (en) * | 2007-10-26 | 2014-07-08 | Glycobiosciences Inc. | Condom with multifunctional coating |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4981686A (en) * | 1987-05-18 | 1991-01-01 | Hardy Robert E | Personal lubricant |
CA1337279C (en) * | 1989-06-06 | 1995-10-10 | Robert J. Borgman | Intravaginal treatment of vaginal infections with buffered metronidazole compositions |
FR2739558B1 (fr) * | 1995-10-05 | 1997-11-28 | Innothera Lab Sa | Forme galenique unitaire pour hormonotherapie locale de la secheresse vaginale |
WO1998018448A1 (de) * | 1996-10-31 | 1998-05-07 | Notax Holding Gesellschaft Mbh | Verwendung von polyäthylenglykol - 9 nonylphenyläther |
US6912944B2 (en) * | 2001-07-25 | 2005-07-05 | Aceram Technologies, Inc. | Ceramic armour systems with a front spall layer and a shock absorbing layer |
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2003
- 2003-05-01 AU AU2003241338A patent/AU2003241338A1/en not_active Abandoned
- 2003-05-01 KR KR1020047017603A patent/KR101046538B1/ko active IP Right Grant
- 2003-05-01 NZ NZ536379A patent/NZ536379A/en not_active IP Right Cessation
- 2003-05-01 CA CA002484329A patent/CA2484329A1/en not_active Abandoned
- 2003-05-01 MX MXPA04010890A patent/MXPA04010890A/es active IP Right Grant
- 2003-05-01 CN CN038158752A patent/CN1665484A/zh active Pending
- 2003-05-01 RU RU2004131858/15A patent/RU2288700C2/ru active
- 2003-05-01 BR BRPI0309768A patent/BRPI0309768B8/pt not_active IP Right Cessation
- 2003-05-01 EP EP03731070A patent/EP1501478A1/en not_active Withdrawn
- 2003-05-01 WO PCT/US2003/013554 patent/WO2003092652A1/en active Application Filing
Also Published As
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RU2288700C2 (ru) | 2006-12-10 |
AU2003241338A1 (en) | 2003-11-17 |
KR101046538B1 (ko) | 2011-07-07 |
WO2003092652A1 (en) | 2003-11-13 |
KR20050062466A (ko) | 2005-06-23 |
CA2484329A1 (en) | 2003-11-13 |
EP1501478A1 (en) | 2005-02-02 |
BR0309768B1 (pt) | 2014-06-24 |
RU2004131858A (ru) | 2005-06-10 |
BRPI0309768B8 (pt) | 2021-05-25 |
NZ536379A (en) | 2006-12-22 |
BR0309768A (pt) | 2005-03-22 |
MXPA04010890A (es) | 2005-07-14 |
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